- 學位論文
第三類 semaphorin及其受體於胰臟外分泌和內分泌腫瘤之表現
Expression of class 3 semaphorins and their receptor complexes in pancreatic exocrine and endocrine tumors
摘要
第三類semaphorin 家族分子及其受體plexin、neuropilin 蛋白所負責的訊息傳遞，其功用不止見於神經系統發育過程中的軸突導引，亦常常在不同種類癌症生成或進展扮演重要功能。胰臟腺癌是一種進展快速、易轉移、且致死率高的癌症，雖然已有諸多關於胰臟腺癌致病及轉移的分子機制研究，但第三類semaphorin 家族分子在胰臟腺癌的表現及其造成之影響，僅只有零星的報導。本論文第一部份主要探討第三類semaphorin及其受體plexin、neuropilin 蛋白在胰臟腺癌表現及調控它們表現的機制，首先我們發現：不同於其他癌症通常只表現少數種第三類semaphorin及其受體，胰臟腺癌的腫瘤標本常可見到五種甚至更多種的第三類semaphorin及其受體表現；而這種多個同家族蛋白分子共同表現的現象，並非源於基因複製，而是因為SOX4這個轉錄分子在胰臟腺癌表現，並提高第三類semaphorin及其受體的基因轉錄。當使用RNAi-knockdown方法抑制SOX4在胰臟腺癌細胞株時，第三類semaphorin及其受體的表現量也隨之降低。抑制SOX4表現的細胞株，生長的速度比控制組緩慢，植入老鼠體內時所形成的腫瘤也較小。臨床上的統計顯示，有SOX4表現的胰臟腺癌，表現較多種類的第三類semaphorin及其受體(P=0.033, NPar Kruskal-Wallis one-way 分析) ，病人的五年存活率也較差 (P =0.0409, Kaplan-Meier分析)；反之，促進SOX4分解的miR-129-2，在這些病例標本的表現量就少。因此，我們可在胰臟腺癌中建立一個調控模式，意即miR-129-2減少，使得SOX4表現增加，而使第三類semaphorin及其受體的轉錄增加。論文第二部份是檢視第三類semaphorin及其受體在胰臟內分泌腫瘤的表現，結果顯示與胰臟腺癌相異的表現模式，並且semaphorin受體之一的neuropilin 2表現於90%以上的胰臟內分泌腫瘤，可能參與胰臟內分泌腫瘤新生血管的機制。
並列摘要
Semaphorin signaling through plexins frequently participates in tumorigenesis and malignant progression in various types of cancer. In particular, the role of semaphorin signaling in pancreatic ductal adenocarcinoma (PDAC) remains unexplored, despite a high likelihood of metastasis and mortality. Unlike other epithelial malignancies that often express a small number of specific genes in the Semaphorin/Plexin family, five or more are often expressed in human PDAC. In the first part of this study, we show that such concomitant expression of these SEMA3/Plexin family members is not a result of gene amplification, but (at least partially) is attributed to increased gene transcription activated by SOX4 neo-expressed in PDAC. Via luciferase promoter activity assay, chromatin-immunoprecipitation, and electrophoresis mobility shift assay, SOX4 is demonstrated to bind to the consensus site at the promoter of each SEMA3 and Plexin gene to enhance transcription activity. Conversely, RNAi-knockdown of SOX4 in PDAC cell lines results in decreased expression of SEMA3/Plexin family members and is associated with restricted tumor growth both in vitro and in SCID mice. Furthermore, SOX4 expression in human PDAC tissues not only parallels with the summed expression of SEMA3/Plexin family members (P=0.033, NPar Kruskal-Wallis one-way analysis) but also correlates with poor survival of PDAC pateints (P=0.0409, Kaplan-Meier analysis). Intriguingly, miR-129-2, which targets SOX4 for degradation, is repressed in some human PDAC cases associated with SOX4 and with a concomitant increase in the expression of SEMA3/Plexin family members. In conclusion, we disclose a miR-129-2/SOX4/Semaphorin-Plexin regulatory axis in the tumorigenesis of pancreatic cancer. The second part of this study focuses on the expression of SEMA3/Plexin family members in much more infrequent pancreatic neuroendocrine tumors (PNETs), which only accounting for 1-2% of all pancreatic neoplasms. Current concepts of PNET tumorigenesis are nourished from the research in pancreatic endocrine cell development and hereditary PNETs associated with multiple endocrine neoplasia type 1 syndrome (MEN 1), but whether the same molecular alternations exist in sporadic PNETs remained less explored. Neuropilin 2 (NRP2), a receptor for axon guidance molecule semaphorins and vascular endothelial growth factor (VEGF), was reported to be expressed in most PNETs; in this part of study, we utilized immunohistochemistry to examine the expression profile of NRP2 ligands and coreceptors in PNETs.
參考文獻
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